Stromal Cell Therapy|Articles in Press

Biodegradable biliary stents coated with mesenchymal stromal cells in a porcine choledochojejunostomy model

Published:February 25, 2023DOI:


      Background aims

      Roux en y anastomosis is a preferred method of biliary reconstruction in liver transplantation that involves living donors or pediatric patients. However, biliary stricture is a frequent and serious complication, accounting for up to 40% of biliary complications in these patients. Previously, we demonstrated that extraluminal delivery of adipose-derived (AD) mesenchymal stromal cells (MSCs) decreased peri-biliary fibrosis and increased neo-angiogenesis in a porcine model of duct-to-duct biliary anastomosis. In this study, we used a porcine model of Roux en y anastomosis to evaluate the beneficial impact of a novel intraluminal MSC delivery system.


      Nine animals were divided into three groups: no stent (group 1), bare stent (group 2) and stent coated with AD-MSCs (group 3). All animals underwent cholecystectomy with roux en y choledochojejunostomy. Two animals per group were followed for 4 weeks and one animal per group was followed for 8 weeks. Cholangiograms and blood were sampled at baseline and the end of study. Biliary tissue was collected and examined by Masson trichrome staining and immunohistochemical staining for MSC markers (CD34 and CD44) and for neo-angiogenesis (CD31).


      Two of three animals in group 1 developed an anastomotic site stricture. No strictures were observed in the animals of group 2 or group 3. CD34 and CD44 staining showed that AD-MSCs engrafted successfully at the anastomotic site by intraluminal delivery (group 3). Furthermore, biliary tissue from group 3 showed significantly less fibrosis and increased angiogenesis compared with the other groups.


      Intraluminal delivery of AD-MSCs resulted in successful biliary engraftment of AD-MSCs as well as reduced peri-biliary fibrosis and increased neo-angiogenesis.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Broelsch C.E.
        • et al.
        Liver transplantation in children from living related donors. Surgical techniques and results.
        Ann Surg. 1991; 214 (discussion 437-9): 428-437
        • Lee S.G.
        A complete treatment of adult living donor liver transplantation: a review of surgical technique and current challenges to expand indication of patients.
        Am J Transplant. 2015; 15: 17-38
        • Fisher R.A.
        Living donor liver transplantation: eliminating the wait for death in end-stage liver disease?.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 373-382
        • Hwang S.
        • et al.
        Long-term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation.
        Liver Transpl. 2006; 12: 831-838
        • Chang J.H.
        • et al.
        Biliary stricture after adult right-lobe living-donor liver transplantation with duct-to-duct anastomosis: long-term outcome and its related factors after endoscopic treatment.
        Gut Liver. 2010; 4: 226-233
        • Zimmerman M.A.
        • et al.
        Development, management, and resolution of biliary complications after living and deceased donor liver transplantation: a report from the adult-to-adult living donor liver transplantation cohort study consortium.
        Liver Transpl. 2013; 19: 259-267
        • Macías-Gómez C.
        • Dumonceau J.M.
        Endoscopic management of biliary complications after liver transplantation: an evidence-based review.
        World J Gastrointest Endosc. 2015; 7: 606-616
        • Noack K.
        • et al.
        The greater vulnerability of bile duct cells to reoxygenation injury than to anoxia. Implications for the pathogenesis of biliary strictures after liver transplantation.
        Transplantation. 1993; 56: 495-500
        • Schwartz D.A.
        • et al.
        Endoscopic therapy of anastomotic bile duct strictures occurring after liver transplantation.
        Gastrointest Endosc. 2000; 51: 169-174
        • Fujiki M.
        • et al.
        Probability, management, and long-term outcomes of biliary complications after hepatic artery thrombosis in liver transplant recipients.
        Surgery. 2017; 162: 1101-1111
        • Girard E.
        • et al.
        Internal biliary stenting in liver transplantation.
        Langenbecks Arch Surg. 2018; 403: 487-494
        • Amador A.
        • et al.
        Clinical trial on the cost-effectiveness of T-tube use in an established deceased donor liver transplantation program.
        Clin Transplant. 2007; 21: 548-553
        • Sun N.
        • et al.
        Biliary tract reconstruction with or without T-tube in orthotopic liver transplantation: a systematic review and meta-analysis.
        Expert Rev Gastroenterol Hepatol. 2015; 9: 529-538
        • Jung S.W.
        • et al.
        Clinical outcome of internal stent for biliary anastomosis in liver transplantation.
        Transplant Proc. 2014; 46: 856-860
        • Berardis S.
        • et al.
        Gene expression profiling and secretome analysis differentiate adult-derived human liver stem/progenitor cells and human hepatic stellate cells.
        PLoS One. 2014; 9: e86137
        • Pittenger M.F.
        • et al.
        Multilineage potential of adult human mesenchymal stem cells.
        Science. 1999; 284: 143-147
        • Zuk P.A.
        • et al.
        Multilineage cells from human adipose tissue: implications for cell-based therapies.
        Tissue Eng. 2001; 7: 211-228
        • Nauta A.J.
        • Fibbe W.E.
        Immunomodulatory properties of mesenchymal stromal cells.
        Blood. 2007; 110: 3499-3506
        • Zhang Y.
        • et al.
        Autologous adipose tissue-derived mesenchymal stem cells introduced by biliary stents or local immersion in porcine bile duct anastomoses.
        Liver Transpl. 2020; 26: 100-112
        • Dietz A.B.
        • et al.
        Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn's disease.
        Gastroenterology. 2017; 153 (e2): 59-62
        • Sharma S.
        • Gurakar A.
        • Jabbour N.
        Biliary strictures following liver transplantation: past, present and preventive strategies.
        Liver Transpl. 2008; 14: 759-769
        • Kohli D.R.
        • et al.
        Patients with post-transplant biliary strictures have significantly higher rates of liver transplant failure and rejection: a nationwide inpatient analysis.
        J Gastroenterol Hepatol. 2021; 36: 2008-2014
        • Rao H.B.
        • et al.
        Endoscopic therapy for biliary strictures complicating living donor liver transplantation: factors predicting better outcome.
        World J Gastrointest Pathophysiol. 2017; 8: 77-86
        • Grolich T.
        • et al.
        Self-expandable biodegradable biliary stents in porcine model.
        J Surg Res. 2015; 193: 606-612
        • Oyagi S.
        • et al.
        Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats.
        J Hepatol. 2006; 44: 742-748
        • Abdel Aziz M.T.
        • et al.
        Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis.
        Clin Biochem. 2007; 40: 893-899
        • Nagaya N.
        • et al.
        Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy.
        Circulation. 2005; 112: 1128-1135
        • Ortiz L.A.
        • et al.
        Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.
        Proc Natl Acad Sci U S A,. 2003; 100: 8407-8411
        • Ninichuk V.
        • et al.
        Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice.
        Kidney Int. 2006; 70: 121-129
        • Yang B.
        • et al.
        Tracking and therapeutic value of human adipose tissue-derived mesenchymal stem cell transplantation in reducing venous neointimal hyperplasia associated with arteriovenous fistula.
        Radiology. 2016; 279: 513-522